Cell migration plays a pivotal role in the development of the nervous system. One of the most striking examples of extensive cell movement is exhibited by the neural crest, a transient cell population that travels long distances, interacts with diverse tissues, and gives rise to an impressive array of derivatives. Failure of neural crest migration contributes to craniofacial malformations such as cleft palate, clinical syndromes such as Waardenburg's, and numerous developmental abnormalities of the central, peripheral, auditory, and enteric nervous systems. The extensive migration of the neural crest is highly unusual. Although the migration pathways and ultimate cell fates of neural crest cells are well understood, the mechanisms of migration have largely been overlooked. Most embryonic and adult cell types migrate only under very specific conditions in vitro, and in a correspondingly restricted number of tissues in vivo. There is considerable evidence that the adhesion of neural crest cells to the extracellular matrix (ECM) is mediated by the integrin family of receptors; however the mechanism by which these cells modulate their integrin-mediated adhesion in order to migrate through changing environments is unknown. Recently, we have demonstrated that avian neural crest cells can adapt to and migrate efficiently on a wide range of ECM concentrations in vitro. Interestingly, the extent of adaptation varies along the anterior/posterior (A/P) axis suggesting that differences in integrin regulation may contribute to differences in neural crest migration that thereafter act to restrict developmental potential. Therefore, the experiments outlined in this proposal intend to examine two mechanisms of neural crest migration by (1) determining whether neural crest cells endocytose integrin receptors in order to regulate their surface ECM receptor levels, and (2) determining how integrin-mediated adhesion regulates the activity of Rho GTPases in migrating neural crest cells. These studies will advance our understanding of the mechanisms of neural crest migration and will help to clarify how these cells contribute to the normal development of the nervous system.